Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

A Randomized Phase 2 KINETIC Trial Evaluating SAGE-324/BIIB124 in Individuals with Essential Tremor.

BACKGROUND: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. OBJECTIVE: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). METHODS: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. RESULTS: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. CONCLUSION: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Self-Administered Screening Questionnaire for Parkinson's Disease-Associated Psychosis (SASPAP).

BACKGROUND: Psychosis is a common manifestation of Parkinson's disease (PD), and a major source of caregiver burden, nursing home placement, and mortality. Psychosis symptoms are often not volunteered during the clinic visit because of embarrassment or lack of insight, and there is no validated screening scale. We compare a new self-administered psychosis screening questionnaire against the Parkinson's Disease Psychosis Scale (PDPS) and physician interview as the gold standard assessments. OBJECTIVE: To create and validate the Self-Administered Screening Questionnaire for PD-Associated Psychosis (SASPAP). METHODS: The questionnaire was developed through a modified Delphi method by a committee of two neurologists, a psychiatrist, a patient, and patient advocate and underwent several rounds of revisions, including patient ß-testing. It was provided by staff at intake to 250 consecutive patients diagnosed with PD, at the Methodist Hospital Movement Disorders Clinic, and separately to their caregivers when available. Later, the PDPS and a general psychosis interview were administered by PD specialists without knowledge of the screening questionnaire responses. RESULTS: Two hundred and fifty consecutive patients with PD (mean age, 68.6 ± 7.0; mean age of PD onset, 62.7 ± 10.5 years; 35.2% female) were included. The screening questionnaire was positive for psychosis (any of the four questions positive) in 33.6% of patients. Compared to the gold standard, the SASPAP sensitivity was 87.8% and the specificity 92.3%. CONCLUSION: This four-question self-administered screening questionnaire for PD psychosis demonstrated high diagnostic accuracy compared with the gold standard assessments and can be self-completed at visit intake. © 2023 International Parkinson and Movement Disorder Society.

THN 102 for Excessive Daytime Sleepiness Associated with Parkinson's Disease: A Phase 2a Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS.

BACKGROUND: Restless legs syndrome (RLS) is a common condition that initially responds dramatically to dopaminergic therapy. Over time, however, dopaminergics cause augmentation, where symptoms occur earlier and intensify. Animal models suggest this may result from increased dopamine receptor type-1 affinity in the spinal cord. Ecopipam is a potent, specific dopamine-1/5 receptor antagonist. METHODS: We performed a small (N = 10) exploratory placebo controlled, cross-over safety trial of ecopipam (25-100 mg/day) for patients with augmented RLS currently taking dopamine agonists. RESULTS: Ecopipam was well tolerated with sedation being the most common adverse event in drug and placebo. Safety scales and serology data were similar to placebo. The study was not powered to demonstrate efficacy and exploratory efficacy data showed no significant improvement compared to placebo, but RLS diaries, the international RLS rating scale, and clinical global impressions all favored drug. No subject worsened on drug or demonstrated rebound worsening after drug discontinuation. CONCLUSION: Ecopipam was safe and well tolerated in this initial study for RLS. Given the lack of alternate options, larger efficacy studies for augmented RLS, and potentially de novo RLS are justified.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Consensus Guidelines on Rodent Models of Restless Legs Syndrome.

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features-in the absence of a face-to-face interview-was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

BACKGROUND AND PURPOSE: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. METHODS: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. RESULTS: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. CONCLUSIONS: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

Restless abdomen: a spectrum or a phenotype variant of restless legs syndrome?

BACKGROUND: With the growing awareness of restless legs syndrome (RLS), sensory disorders similar to RLS but initially confined to the arms, abdomen, and perineum have been reported. One of them is restless abdomen, which refers to a restless sensation in abdomen. Our study is designed to evaluate the clinical phenotype of restless abdomen and investigate its relationship with RLS. METHODS: We enrolled 10 patients with restless abdomen according to RLS diagnostic criteria, excluding the requiring of leg involvement. Laboratory examinations were performed to exclude mimics and notable comorbidities. RESULTS: All 10 patients had RLS like symptoms in the abdomen and otherwise satisfied all other RLS diagnostic criteria, and responded to dopaminergic therapy. CONCLUSIONS: Neurologists and gastroenterologists should be aware that RLS-related restlessness can occur in extra-leg anatomy in the absence of episodes of worsening or augmentation of restlessness.

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

Restless legs syndrome in end stage renal disease patients undergoing hemodialysis.

BACKGROUND: The prevalence of Restless legs syndrome (RLS) in End Stage Renal Disease (ESRD) patients is higher than that in the general population. However, the associations of RLS within the ESRD population are inconsistent and RLS is usually neglected in dialysis centers, although it impairs the life quality among ESRD patients. We aim to investigate the prevalence of RLS in patients with ESRD undergoing maintenance hemodialysis and evaluate the risk factors of developing RLS and the effect of RLS on quality of life among ESRD patients. METHODS: ESRD patients undergoing maintenance hemodialysis in Shanghai General Hospital dialysis unit from July 2016 to October 2016 were enrolled in the study. RLS was diagnosed according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). IRLSSG Severity Scale was used to evaluate the severity of RLS. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality, and Hospital Anxiety and Depression Scale (HADS) was used to estimate anxiety and depression. Serologic and historic variables were analyzed to determine predictors of RLS in the ESRD population. RESULTS: A total of 137 ESRD patients were enrolled. The prevalence of RLS among the ESRD patients was 20.44%. The risk of RLS was increased significantly in females (OR = 2.729, p = 0.032) and daily alcohol drinkers (OR = 4.716, p = 0.022). RLS increased the risks of sleep disorders (25/28, 89.3% vs 73/109, 67.0%, p = 0.02) and sedative hypnotics intake (7/28, 25.0% vs 10/109, 9.2%, p = 0.047) and impaired the sleep quality (7/109 vs 11/28, p = 0.001) according to PSQI sum scores. CONCLUSION: A high RLS prevalence among the ESRD patients undergoing hemodialysis was confirmed. ESRD patients who are women and drinking alcohol have a higher risk of RLS. The sleep quality was significantly impaired and sleeping medication use was more common among the ESRD patients with RLS.

Systematic Literature Review of Quetiapine for the Treatment of Psychosis in Patients With Parkinsonism.

OBJECTIVE: The purpose of this article was to determine the efficacy and tolerability of quetiapine compared with placebo or other interventions for psychosis in parkinsonism. METHODS: Participants with a diagnosis of parkinsonism participated in randomized controlled trials (RCTs) investigating the efficacy and tolerability of quetiapine for psychotic symptoms within a defined follow-up period. The authors conducted searches on PubMed, Cochrane Controlled Register of Trials, and EMBASE for articles published from January 1991 to October 2017. Study methodology and patient- and treatment-level data were independently extracted and summarized by using descriptive statistics. Studies underwent quality assessment for risk of bias. RESULTS: A total of 17,615 unique records were identified, and seven RCTs (total N=241) met inclusion criteria. Five RCTs were placebo controlled, and two compared quetiapine against clozapine. The mean study duration was 12 weeks, and the mean daily quetiapine dose was 103 mg per day (range, 12.5-300 mg). In four of five placebo-controlled RCTs, quetiapine failed to demonstrate significant improvement of psychosis in parkinsonism compared with placebo. In two clozapine-comparator RCTs, quetiapine was better tolerated but no more effective than clozapine. Across all RCTs, the mean completion rates for quetiapine, clozapine, and placebo were 66%, 68.5%, and 66%, respectively. Quetiapine did not significantly worsen motor function. CONCLUSIONS: The efficacy of quetiapine in RCTs for psychosis in parkinsonism is no better than that for placebo or clozapine. On the basis of novel data, clinicians should reevaluate traditional viewpoints on the benefits of quetiapine for psychosis in parkinsonism.

Treating Hallucinations and Delusions Associated With Parkinson's Disease Psychosis.

PURPOSE OF REVIEW: We discuss features of Parkinson's disease psychosis (PDP) including symptomology and pathophysiology. Treatment options, including non-pharmacologic strategies, dose reduction of offending agents, and the addition of non-dopaminergic antipsychotics, are addressed. The efficacy of second-generation antipsychotics and novel agents is examined. RECENT FINDINGS: Pimavanserin, a 5-HT2A/C receptor inverse agonist with no other receptor activity, has shown efficacy and tolerability and is now FDA approved for PDP treatment. Research into novel targets is ongoing. PDP is a morbid complication of Parkinson's disease with complex incompletely understood mechanisms. Treatment is directed towards mitigation of psychosis without worsening of motor features.

A 500 U/2 mL dilution of abobotulinumtoxinA vs. placebo: randomized study in cervical dystonia.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs. MATERIALS AND METHODS: We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4. RESULTS: A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P < 0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients. CONCLUSIONS: This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Psychiatric associations of adult-onset focal dystonia phenotypes.

BACKGROUND: Depression and anxiety frequently accompany the motor manifestations of isolated adult-onset focal dystonias. Whether the body region affected when this type of dystonia first presents is associated with the severity of these neuropsychiatric symptoms is unknown. OBJECTIVES: The aim of this study was to determine whether depression, anxiety and social anxiety vary by dystonia onset site and evaluate whether pain and dystonia severity account for any differences. METHODS: Patients with isolated focal dystonia evaluated within 5 years from symptom onset, enrolled in the Natural History Project of the Dystonia Coalition, were included in the analysis. Individual onset sites were grouped into five body regions: cervical, laryngeal, limb, lower cranial and upper cranial. Neuropsychiatric symptoms were rated using the Beck Depression Inventory, Hospital Anxiety and Depression Scale and Liebowitz Social Anxiety Scale. Pain was estimated using the 36-Item Short Form Survey. RESULTS: Four hundred and seventy-eight subjects met our inclusion criteria. High levels of depression, anxiety and social anxiety occurred in all groups; however, the severity of anxiety and social anxiety symptoms varied by onset site group. The most pronounced differences were higher anxiety in cervical and laryngeal, lower anxiety in upper cranial and higher social anxiety in laryngeal. Increases in pain were associated with worse neuropsychiatric symptom scores within all groups. Higher anxiety and social anxiety in laryngeal and lower anxiety in upper cranial persisted after correcting for pain and dystonia severity. CONCLUSION: Anxiety and social anxiety severity vary by onset site of focal dystonia, and this variation is not explained by differences in pain and dystonia severity.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management.

Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep. It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome. Dopamine agonists and calcium channel apha-2-delta antagonists (gabapentin, gabapentin enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms. Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible. Iron supplements are started when the serum ferritin concentration is ≤75 µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines.